John R. Brandt

Risk Factors for the Hemolytic Uremic Syndrome in Children Infected with Escherichia coli O157:H7: a Multivariable Analysis

BACKGROUND Escherichia coli O157:H7 is the leading cause of hemolytic uremic syndrome (HUS). Risk factors for development of this complication warrant identification. METHODS We enrolled children infected with E. coli O157:H7 within 1 week of the onset of diarrhea in this prospective cohort study. The study was conducted in 5 states over 9.5 years . The primary and secondary outcomes were HUS (hematocrit <30% with smear evidence of hemolysis, platelet count <150 × 10(3)/µL, and serum creatinine concentration > upper limit of normal for age) and oligoanuric HUS. Univariate and multivariable and ordinal multinomial regression analyses were used to test associations between factors apparent during the first week of illness and outcomes. RESULTS Of the 259 children analyzed, 36 (14%) developed HUS. Univariate analysis demonstrated that children who received antibiotics during the diarrhea phase more frequently developed HUS than those who did not (36% vs 12%; P = .001). The higher rate of HUS was observed across all antibiotic classes used. In multivariable analysis, a higher leukocyte count (adjusted odds ratios [aOR] 1.10; 95% CI, 1.03-1.19), vomiting (aOR 3.05; 95% CI, 1.23-7.56), and exposure to antibiotics (aOR 3.62; 95% CI, 1.23-10.6) during the first week of onset of illness were each independently associated with development of HUS. Multinomial ordinal logistic regression confirmed that initial leukocyte count and antibiotic use were independently associated with HUS and, additionally, these variables were each associated with the development of oligoanuric HUS. CONCLUSIONS Antibiotic use during E. coli O157:H7 infections is associated with a higher rate of subsequent HUS and should be avoided.

Escherichia coli O157:H7–associated hemolytic-uremic syndrome after ingestion of contaminated hamburgers

We conducted a retrospective analysis of 37 children with Escherichia coli O157:H7-associated hemolytic-uremic syndrome. The infection was traced to contaminated hamburgers at a fast-food restaurant chain. Within 5 days of the first confirmed case, the Washington State Department of Health identified the source and interrupted transmission of infection. Ninety-five percent of the children initially had severe hemorrhagic colitis. Nineteen patients (51%) had significant extrarenal abnormalities, including pancreatitis, colonic necrosis, glucose intolerance, coma, stroke, seizures, myocardial dysfunction, pericardial effusions, adult respiratory disease syndrome, and pleural effusions. Three deaths occurred, each in children with severe multisystem disease. At follow-up two children have significant impairment of renal function (glomerular filtration rate < 80 ml/min/per 1.73 Hm2); both of these children have a normal serum creatinine concentration. Hemolytic-uremic syndrome is the most common cause of acute renal failure in children, and this experience emphasizes the systemic nature of this disease. Clinicians should anticipate that multisystem involvement may occur in these patients, necessitating acute intervention or chronic follow-up. This outbreak of Hemolytic-uremic syndrome also highlights the microbiologic hazards of inadequately prepared food and emphasizes the importance of public health intervention in controlling Hemolytic-uremic syndrome.

Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation

The mortality rate in children with ESRD is substantially lower than the rate experienced by adults. However, the risk of death while awaiting kidney transplantation and the impact of transplantation on long‐term survival has not been well characterized in the pediatric population. We performed a longitudinal study of 5961 patients under age 19 who were placed on the kidney transplant waiting list in the United States. Of these, 5270 received their first kidney transplant between 1990 and 2003. Survival was assessed via a time‐varying nonproportional hazards model adjusted for potential confounders. Transplanted children had a lower mortality rate (13.1 deaths/1000 patient‐years) compared to patients on the waiting list (17.6 deaths/1000 patient‐years). Within the first 6 months of transplant, there was no significant excess in mortality compared to patients remaining on the waiting list (adjusted Relative Risk (aRR) = 1.01; p = 0.93). After 6 months, the risk of death was significantly lower: at 6–12 months (aRR = 0.37; p < 0.001) and at 30 months (aRR 0.26; p < 0.001). Compared to children who remain on the kidney transplant waiting list, those who receive a transplant have a long‐term survival advantage. With the potential for unmeasured bias in this observational data, the results of the analysis should be interpreted conservatively.

Lessons learned in the management of hemolytic uremic syndrome in children

Escherichia coli O.157:H7 is a serious and common human pathogen that can cause diarrhea, hemorrhagic colitis, and the hemolytic uremic syndrome (HUS). During a massive outbreak of infection with E coli O157:H7 in January 1993 in Washington State, more than 600 people, mostly children, acquired symptomatic infection, and 37 were hospitalized with HUS at Childrens Hospital and Medical Center in Seattle, and six at other hospitals in Washington. Twenty-one (57%) required dialysis. Nineteen (51%) had significant extrarenal pathology: gastrointestinal in 14 patients (38%), cardiovascular in 13 (35%), pulmonary in 9 (24%), and neurological in 6 (16%). Most patients were managed nonoperatively, but three required total abdominal colectomy and one a left colectomy. No child had perforation. Three patients died, all of whom had multisystem disease. The authors recommend (1) that all patients with bloody diarrhea undergo microbiological evaluation for E coli O157:H7 before any surgical intervention; (2) avoidance of antibiotics and antimotility agents in patients with proven or suspected infection with E coli O157:H7 until the safety and efficacy of such interventions have been established in controlled trials; (3) that patients with E coli O157:H7 infections be evaluated for microangiopathic changes consistent with HUS in the week after onset of diarrhea; (4) nasogastric suction for severe symptoms, and frequent abdominal evaluations, tests (electrolytes/amylase), and roentgenograms to exclude treatable abdominal disorders; and (5) institution of hemodialysis for oliguria/anuria, acidosis, or rising creatinine. The authors recommend surgical exploration for toxic megacolon, colonic perforation, acidosis unresponsive to dialysis, or recurrent signs of obstruction or colonic stricture.

Needle Phobia and Stress-Reducing Medical Devices in Pediatric and Adult Chemotherapy Patients

Needle phobia—fear of medical devices—is a significant problem in pediatric and adult chemotherapy patients. Stress-reducing medical devices is a new, effective cognitive therapy for needle phobia. Twenty-five pediatric and 25 adult chemotherapy patients were randomly exposed to conventional or stress-reducing decorated butterfly needles and syringes. Emotional stress responses were determined with the Visual Aversion Scale, Visual Analogue Fear Scale, Visual Analogue Anxiety Scale, and Visual Overall Stress Score for each needle and syringe design. Sixty-eight percent of the pediatric and 52% of the adult patients were overtly needle phobic, but children demonstrated significantly more aversion and stress (P < .001). Stress-reducing medical devices effectively and significantly reduced aversion, anxiety, fear, and overall stress, and were 76% effective in preventing overt needle phobia in children and 92% effective in adults (P < .001). One hundred percent of children and adults felt that stress-reducing medical devices should be available in chemotherapy clinics. Needle phobia and stress in pediatric and adult chemotherapy patients are significantly reduced by the use of stress-reducing medical devices.

Cholelithiasis following Escherichia coli O157:H7-associated hemolytic uremic syndrome.

Abstract. Sequelae of Escherichia coli O157 : H7-associated hemolytic uremic syndrome (HUS) 2 – 3 years following an outbreak in Washington State have been prospectively studied to identify predictors of adverse sequelae. Logistic regression analysis was used to examine associations between findings in the acute course and long-term renal and gastrointestinal outcomes. Twenty-one percent of patients had gastrointestinal sequelae, which included cholelithiasis resulting in cholecystectomy (3/29), persistent pancreatitis (2/29), late colon stricture (1/29), and/or glucose intolerance (1/29). Logistic regression analysis found long-term gastrointestinal sequelae were higher in patients who, during HUS, had hypertension [odds ratio (OR) = 21.2, 95% confidence interval (CI) = 1.9 – 164.4, P = 0.01] or gastrointestinal complications (OR = 21.2, 95% CI = 1.9 – 164.4, P = 0.01). Renal sequelae were seen in 35% of patients. One patient (4%) had persistent hypertension and 9 (31%) had minor urinary findings (hematuria or proteinuria). Thrombocytopenia lasting longer than 10 days during the acute illness was associated with a risk for subsequent renal sequelae (OR = 15.0, 95% CI = 1.98 – 1,703.0, P = 0.009). We conclude a high incidence of gastrointestinal sequelae, especially cholelithiasis presenting long after the acute illness, may be seen with HUS. The short follow-up period may underestimate the extent and severity of eventual renal sequelae.

Improved outcome of young children on nightly automated peritoneal dialysis

We reviewed our center’s experience with nightly automated peritoneal dialysis (APD) as maintenance renal replacement therapy (RRT) for infants and children under the age of 5 years and compared it with national dialysis and transplant data. A retrospective chart review of 19 consecutive patients with the onset of end-stage renal disease (ESRD) before 5 years of age (mean = 1.8 years) between June 1988 and June 1994 was performed. All patients received nightly APD, supplemental feedings, calcitriol, erythropoietin, and 10 of 19 were on growth hormone (rhGH) therapy. The growth of our patients was maintained or improved during the study period, with the 10 of 19 on rhGH gaining a mean of one standard deviation in height when followed for 2 years. Our school-age children were all in age-appropriate classes. There were no deaths in our group; the incidence of peritonitis was lower than in national data. We conclude that APD is a realistic option for the treatment of ESRD in the 0- to 5-year-old child. Because of the improved graft and patient survival in older children, APD in a specialized center might be the RRT of choice in this age group, allowing good growth and development while maximizing the chances of an eventual and successful renal transplant.

Glomerular Filtration Rate in Children with Solid Tumors: Normative Values and a New Method for Estimation

Many chemotherapy regimens used in children are nephrotoxic. Accurate dosing of these medications requires that some estimation of glomerular filtration rate (GFR) be performed prior to initiating chemotherapy. However, few studies evaluating normal GFR in children exist. The authors report normal values for GFR for children with nonhematogenous malignancies using a highly accurate method of directly measuring GFR and an equation for estimating absolute GFR in these children. Children with nonhematogenous malignancies with no evidence of renal involvement or prior use of nephrotoxic agents had their GFR measured using an iothalamate infusion methodology. A total of 111 children (males and females) with a mean age = 7.95 years (range 2.8 months-19.5 years) were included in the study. GFR adjusted for body surface area (mL/min/1.73 m 2 ) increases in the first 2 years of life and then plateaus at a level comparable to adult values. GFR adjusted for body surface area for males >2 years = 131.3 - 22.5, females = 126.8 - 24.4 mL/min/1.73 m 2 ( p value not significant). Absolute GFR in mL/min can be easily estimated by a simple formula ( r 2 = .97) based on the childs weight and serum creatinine: \[ \hbox{\itshape GFR (mL/min)} = {\rm k} \sqrt{\frac{(\hbox{\itshape agemos}+\hbox{\itshape 6}\kern2pt)*{\hbox{\itshape wt}}}{{\hbox{\itshape Cr}_{\hbox{\fontsize{6}{6}\selectfont\itshape serum}}}}} \] where agemos is age in months, wt is weight in kg, and k = 1.05 for males and 0.95 for females. The accurate measurement of GFR remains vitally important in the safe and effective treatment of pediatric solid tumors. This study provides a set of normal GFR values for these children and an equation for easy estimate of absolute GFR.

Estimating absolute glomerular filtration rate in children

Normal values of glomerular filtration rate (GFR) in children are often expressed in a value adjusted to adult ideal body surface area. These values work well for many clinical situations, but in infants and children, especially those with atypical body mass, they may not accurately reflect renal function. Most body composition values in children are expressed in developmentally appropriate ranges. Absolute GFR (ml/min) also changes during childhood increasing rapidly in infancy and then gradually with age and body size. Previously, we developed a bedside equation for estimating GFR (ml/min) in children that accounted for changes with age and body size, and which correlated well with steady-state cold iothalamate GFR (ml/min) measurements: GFR (ml/min) = k*sqrt[(age(months) + 6)*wt (kg)/serum Cr (mg/dl)], where k=0.95 for females and 1.05 for males. In the present study GFR (ml/min) measured by iothalamate infusion was compared by correlation analysis with estimates calculated from the above equation in 566 children. This equation provides clinicians with a simple bedside method to estimate absolute GFR (ml/min).

Intraperitoneal erythropoietin in children on peritoneal dialysis: A study of pharmacokinetics and efficacy.

The pharmacokinetics and efficacy of intraperitoneal (IP) recombinant human erythropoietin (rHuEPO) were investigated in children undergoing chronic peritoneal dialysis. Eight children were administered a single dose of 100 U/kg of rHuEPO IP with 50 mL of dialysate into a dry peritoneal cavity after nighttime peritoneal dialysis. Serum erythropoietin (EPO) levels were measured at 0, 8, 12, and 24 hours. A mean peak EPO level of 187 mU/mL was obtained at 12 hours. The area under the curve was 5,818 mU/h/mL, and relative bioavailability was similar to that found using subcutaneous (SC) dosing. Nine children completed 11 to 12 weeks of IP rHuEPO therapy. The patients maintained a normal hematocrit (34% +/- 2.3%) with a mean final IP rHuEPO dosage that was not significantly greater than the mean previous SC dosage (IP, 290 +/- 194 U/kg/wk; SC, 279 +/- 126 U/kg/wk; P = not significant). There appeared to be a trend for a slightly increased risk for peritonitis compared with historical controls at our center (relative risk = 3.1; 95% confidence interval, 0.92 to 6.3). IP rHuEPO is effective in children undergoing continuous cycling peritoneal dialysis without requiring increased rHuEPO dosages, but the possibility of an increased risk for peritonitis will need to be further explored.